GHRP-6 (Growth Hormone Releasing Peptide-6)

GHRP-6 is a synthetic hexapeptide that stimulates the secretion of growth hormone (GH). It mimics the action of ghrelin, a hormone that binds to the growth hormone secretagogue receptor (GHSR1a). Its main activity, the stimulation of GH secretion, leads to several downstream effects, including an increase in expression of IGF-1. 

It exerts protective effects on various tissues such as the heart, brain, and gut. Its potential to be used as a therapeutic agent is currently under research, with clinical studies being conducted.

Mechanism of Action

Although GHRP-6 acts mainly by stimulating the release of GH, it is able to exert benefits that extend beyond growth alone. The main mechanisms by which it exerts its effects include:

• Stimulation of GH: It binds to the growth hormone secretagogue receptor (GHS-R) in the hypothalamus [1] and also acts on the pituitary to promote GH secretion [2]. This increases myocyte differentiation and the expression of myogenic markers, IGF-1 (Insulin-like Growth Factor 1) and type I collagen in muscle cells. It upregulates IGF-1 expression in certain regions of the brain, such as the hypothalamus, cerebellum, and hippocampus.
• Modulation of calcium signalling in the brain: This influences physiological processes such as circadian rhythm and neuronal activity [3].
• Modulation of the immune-inflammatory response: By acting through receptors such as CD36, it can attenuate inflammation [4].
• Modulation of gene expression: It alters gene expression involved in fibrosis, tissue remodelling, cell survival, and maintenance of mitochondrial integrity [5]. 
• Activation of neurons in the hypothalamus: This alters feeding behaviour, increasing appetite [6].
• Modulation of metabolism: The effect that GHRP-6 can have on metabolism is dependent on the current metabolic state. When in a fasted state, it stimulates the release of GH, which influences glucose and lipid metabolism to conserve protein [7], while in nonfasted subjects that are already insulin-resistant and/or diabetic, it promotes the gain of fat mass and exacerbates insulin resistance [8].
• Activation of cholinergic pathways: It appears to act on cholinergic pathways in the enteric nervous system to promote gut motility [9].

Overall, GHRP-6 stimulates GH release, which in turn upregulates the expression of IGF-1. This increase in IGF-1 is responsible for benefits such as neuroprotection, cell survival, and tissue regeneration, but GHRP-6 also acts directly to modulate immune responses, stimulate appetite, and influence other hormones and signalling pathways. 

Therapeutic Potential

Given these mechanisms of action, GHPR-6 could potentially be used for therapeutic purposes, for which it is currently being investigated in preclinical and clinical studies. Some of the possible therapeutic uses include:

• Muscle growth: It can increase appetite and prevent the breakdown of muscle tissue by increasing the secretion of GH7.
• Neuroprotection: It has been found to protect the brain from excitotoxicity [10] and modulate addiction [11]. It has also been studied as part of a combination therapy for stroke, where, when combined with epidermal growth factor, it can reduce brain infarct size and improve neurological outcomes [12].
• Cardioprotection: It has demonstrated an ability to protect the heart from damage induced by doxorubicin. It can reduce cell death, fibrosis, and oxidative stress, which helps to preserve heart function [5].
• Fibrotic disorders: It helps to reduce fibrotic tissue formation in conditions such as liver cirrhosis [13] and skin fibrosis [14].
• Wound healing: It promotes healing and reduces scarring [4].
• Increase gastric emptying: This is useful in the treatment of conditions such as gastroparesis, which can occur due to diabetes [9]. It may also help with other gut motility disorders [15].

Safety

Studies have found that GHRP-6 is generally well-tolerated with very few serious side effects. Since it promotes the release of hormones, there is a possibility that it may alter levels of growth hormone, cortisol, and prolactin, which could alter metabolism and the endocrine system.

How It Compares to GHRP-2

Both GHRP-6 and GHRP-2 act through the same receptor to stimulate the release of GH, which leads to an increase in IGF-1. Co-administration does not provide any enhanced GH release [16].

Despite these similarities, these two peptides have distinctively different applications. GHRP-6 has cardioprotective, appetite-stimulating, and immunomodulatory activity, while GHRP-2 more potently stimulates the release of GH [17].

Data Sheet

Conclusion

GHRP-6 is a potent stimulator of growth hormone release that is best known for its ability to promote wound healing, muscle growth, and its protective action towards the heart, organs, and brain. The effect it has on the body is dependent on metabolic state, with the greatest beneficial effects being seen in fasted subjects. It is being investigated for its therapeutic potential in preclinical and clinical studies, with results showing great promise. 

References

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3. Zhou L, Gao Q, Zhang P, et al. Activation of growth hormone secretagogue receptor induces time-dependent clock phase delay in mice. Am J Physiol-Endocrinol Metab. 2014;307(6):E515-E526. doi:10.1152/ajpendo.00535.2013
4. Mendoza Marí Y, Fernández Mayola M, Aguilera Barreto A, et al. Growth Hormone-Releasing Peptide 6 Enhances the Healing Process and Improves the Esthetic Outcome of the Wounds. Plast Surg Int. 2016;2016:1-11. doi:10.1155/2016/4361702
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